CZ20031896A3 - Process for preparing steroid hormone products comprising a stabilizing agent in non-crystalline form - Google Patents

Abstract

The present invention relates to steroid hormone products, such as oral contraceptive products, including at least one steroid active ingredient mixed with an excipient and having improved dissolution and release rate properties. The invention further relates to methods for making such steroid hormone products, wherein a mixture of the hormone and the excipient is subjected to sufficient mechanical energy to form a powder blend wherein the hormone is stabilized by the excipient in substantially non-crystalline form.

Description

Steroid hormonal preparations and methods of their preparation

Technical field

The invention relates to formulations containing steroid hormones comprising at least one steroid active ingredient mixed with an additive having improved solubility and release rate of the active ingredient. The invention further relates to processes for the preparation of said steroid hormone-containing formulations comprising either solvent-free or non-solvent-based processes.

The term steroid hormone formulation used in this application means a physically discrete unit which is a suitable unit dose dosage form for administration to a human host. Said compositions contain a predetermined amount of at least one steroid hormone as an active ingredient suitable to produce the desired effect. Examples of said formulations include tablets, capsules, capsules, pills or tablets. split powders.

BACKGROUND OF THE INVENTION

Orally administered contraceptives became available in the early 1960s. Since then, more readily available methods have been found to control ovulation and achieve contraception by hormone administration. Oral contraceptives usually contain estrogen and gestagen. In addition to said active steroid ingredients, the contraceptive may contain ingredients including various types of lactose, additives and fillers such as pregelatinized starch and magnesium stearate, and colorants such as an alumina dye.

On an industrial scale, the preparation of preparations • · · ·

containing steroid hormones such as oral contraceptives containing steroids as active ingredients for many years have generally used the solvent-based methods referred to herein as wet processes. According to a method generally known in the art, an active ingredient such as a steroid hormone is dissolved in a suitable volatile solvent and sprayed onto a carrier pharmaceutically acceptable excipient in powder form until the desired concentration per unit weight of said powder is achieved. In general, a solvent is used which is compatible with the active ingredient and the selected excipient and which can be removed under conditions not leading to degradation of the active ingredient. Particularly suitable solvents for use in conjunction with steroid hormones as active ingredients include alcohols such as methanol, ethanol and propanol, ketones such as acetone, hydrocarbons such as ethylene chloride and chloroform, and mixtures of one or more of said solvents with water. Typically, the solution is sprayed onto a bed of powder additive in a suitable processor such as a V-mixer with an auxiliary rod stirrer to intensify the effect or a fluid bed processor. The solution and powder are vigorously mixed in the processor to ensure homogeneous distribution of the active ingredient into the ingredient. After mixing, the solvent is removed by heat and / or reduced pressure to dry the mixture.

An alternative method to wet processes is a process known to those skilled in the art as high shear wet granulation, where the solution is not sprayed on the additive, but is instead blended directly with the powder adjuvant in a high shear mixer. After mixing, the solvent is removed as described above to dry the mixture.

• · * * * _{β β β β β β β β β β β}

Wet processes have many advantages, including the advantages that powder mixtures have a homogeneous distribution of the active ingredient and that they are subject to minimal particle agglomeration under normal storage and handling conditions. Formulations containing steroid hormones prepared from these mixtures have excellent content uniformity.

A major disadvantage of the above solvent-based processes is that in cases where the steroid active ingredient has poor water solubility, environmentally undesirable solvents must be used. Such solvents are often hazardous in terms of handling safety and, in addition to these risks, they are released into the atmosphere. Health regulatory authorities have increasingly objected to the use of these solvents due to their toxicity and mutagenicity.

It follows from the above that for active ingredients that otherwise require treatment with an organic solvent, a dry granulation process or a direct compression process would be preferred. Dry granulation or direct compression methods are hereinafter referred to as dry processing. Dry-treatment processes usually involve even fewer steps than solvent-based wet processes and there is no need to use elevated processing temperatures where such conditions may reduce the efficiency of the thermally sensitive active ingredients. Said dry treatments are also particularly suitable for the preparation of products containing moisture-sensitive steroid hormones associated with granulation in the presence of water. The possibility of omitting the use of expensive organic solvents and the necessary subsequent steps for their evaporation is therefore also very economically attractive.

U.S. Patent No. 5,382,434 proposes the preparation of solvent-free medicaments containing steroids (eg, gestagen and / or estrogen) and an additive (eg, lactose). According to the '434 patent, at least 80% of the steroids must be bound to the additive and the additive must have a low dispersion potential which is assessed by content uniformity. The additive is mixed with the steroid until a homogeneous mixture is obtained. However, the above-mentioned '434 patent does not disclose the release properties of the active ingredient from said compositions, but only describes the mechanical interactions during mixing processing.

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It will be apparent to those skilled in the art that the known formulations of steroid hormones have multiple drawbacks that are not attributable to either wet or dry processing methods. Steroids may exist in various polymorphic forms which, in this specification, include crystalline forms, amorphous forms, and solvates. In the case of wet processing, it is impossible to identify the polymorphic form (s) of the active steroid compound (s) present in the product containing said hormone after removal. organic solvent is a potential problem both in terms of subsequent physical / chemical stability and in terms of subsequent biopharmaceutical properties. Unfortunately, even known dry-processing methods do not completely eliminate the potential existence of polymorphic forms.

In addition, formulations containing steroid hormones prepared by both wet and dry methods may exhibit bioavailability problems. Before a drug administered orally in solid form can be absorbed, it must first be dissolved in the gastrointestinal medium and then transferred in the dissolved state through the gastrointestinal mucosa to the bloodstream. In the substitute test evaluation ·· ·· · ..

For bioavailability, regulatory authorities have a common requirement that at least 80% of the active ingredient contained in the product must be dissolved in a physiologically relevant medium, ie an in vitro dissolution medium, within 60 minutes. Low active ingredient steroid formulations prepared by known methods either by wet or dry methods exhibit undesirable variability in release rates as determined by dissolution evaluation methods in an aqueous medium containing a surfactant. In particular, when considered on a large scale, low steroid formulations produced by dry-processing and intended as oral contraceptives have lower dissolution rates or at least have poorly reproducible dissolution curves.

Steroid hormones such as estrogens and gestagens are also used in hormone replacement therapy (HRT). Formulations containing steroid hormones used for HRT may contain up to 10 times the amount of estrogen and usually less gestagen than oral contraceptives. Accordingly, the above products may also exhibit dissolution problems. In the above-mentioned formulations for HRT steroid hormone replacement therapy, it would also be desirable to overcome the above problems.

SUMMARY OF THE INVENTION

The invention provides a composition comprising a steroid hormone having improved solubility and improved release rate. Said composition comprises at least one steroid hormone in substantially non-crystalline form in admixture with a primary excipient which stabilizes the steroid in its substantially non-crystalline form. The steroid hormone-containing products of the invention have highly favorable dissolution characteristics.

The preferred excipient of the invention is lactose, but the invention is not limited to the use of lactose and other excipients known in the art including dextrose, fructose, sorbitol, xylitol, sucrose, mannitol, dextrate, cellulose, starch and combinations of two or more of the above ingredients.

The steroid hormone formulations of the invention are particularly suitable as either oral contraceptives or HRT formulations. In a preferred embodiment of the above aspect of the invention, the composition is an oral contraceptive containing from about 10 µg to about 50 µg estrogen and / or from about 50 µg to about 300 µg gestagen. The gestagen is preferably selected from the group consisting of norgestimate, norgestrel, levonorgestrel, norethindrone or desogestrel, and the estrogen is preferably selected from the group consisting of ethinylestradiol, estradiol, estopipate or mestranol.

A second aspect of the invention is that it provides a process for preparing said steroid hormone-containing compositions comprising preparing a composition comprising at least one steroid hormone and an additive, preferably lactose, and providing said composition with an amount of mechanical energy sufficient to obtain an additive / steroid powder composition. which is a steroid stabilized by the additive in a substantially non-crystalline form. Advantageously, a mechanical energy of 0.1 hp-min / kg is transmitted to said mixture. Any high-energy processing method may be used to impart mechanical energy by the method of the invention. One method of delivering sufficient mechanical energy involves high-energy mixing of lactose and steroid, but other high-energy methods may also be used.

mixing known in the art comprising co-milling or grinding said mixture.

Preferably, the above composition is prepared in a ratio of steroid hormone to additive in a ratio ranging from about 1/1 to about 1/10. However, it should be noted that the invention is not limited to the above-mentioned range of hormone / ingredient ratios and other hormone / ingredient ratios may be used depending on the desired hormone concentration in the final product. Usually the ratio of steroid to ingredient is the same as in the final product. However, it should be appreciated that it is possible to first prepare a mixture of steroid hormone and an additive, and then add other ingredients to prepare the final mixture. The final mixture is then subjected to a high-energy treatment with the transmission of sufficient mechanical energy according to the invention.

According to one preferred embodiment of the invention, the steroid / additive composition is prepared by a standard wet processing method. For example, a solution of at least one steroid is prepared by dissolving it in a suitable solvent which is then sprayed onto the additive in powder form. The solution and the additive are mixed in a suitable processing apparatus to ensure a homogeneous distribution of the solvent into the additive. The resulting mixture is then dried to remove the solvent by either heat and / or reduced pressure. Then, said mixture is treated with the transmission of mechanical energy as described above to obtain a steroid / additive powder mixture. In a further preferred embodiment of the invention, the steroid and the additive are mixed by a standard dry design where the mixture is then treated with the transfer of mechanical energy as described above to obtain a steroid / additive powder mixture.

DETAILED DESCRIPTION OF THE INVENTION &_lt; _RTI ID = 0.0 _> _{M &lt}; / _{RTI >}

The following expressions have the following meanings, unless the context clearly dictates otherwise:

The term low or low solubility is given to substances that are only slightly soluble or insoluble as defined in the USP.

USP term number of parts of solvent needed to dissolve 1 part solute mg / ml equivalent slightly soluble from 30 to 100 33.3 mg / ml-10 mg / ml slightly soluble from 100 to 1000 10 mg / ml -1 mg / ml very hard soluble from 1000 to 10,000 1 mg / ml-0.1 mg / ml practical insoluble 10,000 or more <0.1 mg / ml

The term content uniformly refers to formulations in which the relative standard deviation of the active ingredient content is ± 1.5%, preferably ± 1.0% and most preferably ± 0.5%.

As noted above, it is known that steroid hormones such as estrogens and gestagens may exist in various forms of solid state and that a particular form of steroid may significantly affect properties such as dissolution rate and physicochemical stability. Two possible consequences of modifying the stable crystalline form of said steroid hormones include increasing the rate and amount of dissolution as well as reducing physical / chemical stability. Generally, a higher energy non-crystalline solid form will exhibit a higher dissolution rate than a more stable lower energy crystalline form.

• · · · · · · · · · · ·

This also applies to certain ingredients such as lactose. Lactose is usually used as an excipient for the preparation of tablets and capsules. Lactose is commercially available in a wide range of varieties including anhydrous and lactose, and lactose monohydrate, anhydrous β-lactose and lactose spray-dried lactose spray-dried lactose (eg FAST-FLO lactose available from Foremost Farms, Baraboo, WI) is usually used as an additive in preparation of direct compression preparations due to its excellent flowability and compression properties.

In particular, this type of lactose contains pure monohydrate and lactose in conjunction with non-crystalline lactose. Said non-crystalline component increases lactose compressibility. Morita et al., Physiochemical Propertise of Crystalline Lactose, II. Effect of Crystallinity on Mechanical and Structural Properties, Chem. Pharm. Bull., Vol. 32, p. 4076 (1984). The non-crystalline state is naturally metastable and recrystallization to a thermodynamically more stable form is inevitable. The tendency of non-crystalline lactose to recrystallise rapidly at an exposure of relative humidity higher than about 60% is well documented. Sebhatu et al., Assessment of the Degree of Disorder in Crystaline Solid by Isothermal Microcalorimetry, International Journal of Pharmaceuticals, Vol.104, p.135 (1994). However, for many drugs, the above process can be delayed by the addition of materials such as microcrystalline cellulose, polyvinylpyrrolidone and citric acid. Buckton et al., The Influence of Additives on Amorphous Spray-Dried Lactose Recrystailization, International Journal of Pharmaceuticals, Vol.121, p.81 (1995).

• · · · ······· «

Various unit operations, including grinding, mixing, wet granulation, drying and pressing, are commonly used in the conventional manufacture of steroid hormone-containing products. Each such process is associated with the incorporation of mechanical and / or thermal energy into the system. This provides the possibility of modifying the various solid state properties of the active ingredients and additives. Hüttenraunch et al., Mechanical Activation of Pharmaceutical Sysdtems, Pharmaceutical research, Vol.2, p.302 (1985). As noted above, these changes can significantly affect product properties such as the rate and extent of dissolution as well as physical / chemical stability (eg conversion to various solid state forms, hydrolysis, etc.). Two possible consequences of modifying a stable crystalline form of material include increasing the rate and extent of dissolution and reducing physicochemical stability. However, it would be highly desirable to increase the rate of dissolution while either improving physical / chemical properties or at least not deteriorating them. The likelihood of modification of a given crystalline form during preparation of a dosage form is directly related to the intrinsic properties of the component to exist in different polymorphic forms.

Norgestimat is an active agent with a gestagenic effect. A thorough investigation of the polymorphic potential of this substance has been demonstrated by the existence of at least two solid forms, a stable crystalline form and a non-crystalline form with higher energy. It is also known that in addition to the stable crystalline form of lactose commonly used in the preparation of tablets, there is a non-crystalline form with higher energy. Similar to lactose, the more energy-intensive, non-crystalline form of norgestimate is produced by physical or mechanical processes. The inventors have found that non-crystalline norgestimate can be recovered from solution by physical means, by rapid evaporation of various organic solvents. It has also been demonstrated in the laboratory that non-crystalline norgestimate can be prepared by ball milling. An apparent decrease in the crystallinity of norgestimate can be observed during the 5 minute grinding. The relative ease of modifying the crystalline structure by mechanical energy as well as the natural content of non-crystalline lactose in conventional types of lactose has led to the assumption that co-processing of lactose and norgestimate could lead to solid solution formation. Theoretically, said solid solution would contain a non-crystalline norgestimate solubilized in the non-crystalline lactose domains and thus form a composition exhibiting faster dissolution rates with possible increased physical / chemical stability.

Considerable efforts have been devoted to the preparation of the non-crystalline form of norgestimate in the presence and absence of lactose by physical and mechanical means. Various mixtures of norgestimate and lactose were prepared. To allow qualitative or semi-quantitative analysis, the components were thoroughly mixed in 1: 1 and 1: 9 ratios either by dissolving them in a mixed co-solvent or by co-milling. Qualitative determination of the degree of crystallinity was performed by powder X-ray diffractometry (PXRD). The minimum detectable concentration of crystalline norgestimate has been shown to be about 3%.

The physical stability of non-crystalline norgestimate and non-crystalline glucose was determined prior to evaluation of drug / additive interactions. The room temperature at various relative humidity (% RH), 0%, 31% and 76% RH was selected as the storage temperature to assess stability. Within three days, amorphous norgestimate was completely recrystallized under all storage conditions. Based on this finding was made

• Assessment of lactose's ability to inhibit recrystallization and increase the physical stability of non-crystalline norgestimate.

Co-precipitation of norgestimate and FAST-FLo lactose from a solvent mixture containing ethanol and water was performed by evaporation of the solvent under reduced pressure. In the presence of lactose, norgestimate remains completely amorphous in the air conditioner for at least 32 days at room temperature and 0% RH. In the absence of glucose, under the same conditions, norgestimate recrystallizes within three days. It was predicted that PXRD analysis of a mixture of norgestimate: FAST FLO lactose at both a 1: 1 and a 1: 9 ratio showed that lactose recrystallized within 1 hour at 75% RH. This was assumed because the non-crystalline lactose undergoes rapid recrystallization at about 60% RH. However, norgestimate partially remains in non-crystalline form at said high relative humidity for at least 6 days. The fact that norgestimate remains in non-crystalline form after lactose recrystallization suggests that the two compounds are solid miscible. These findings further support the hypothesis that dissolution of lactose and norgestimate in a water-alcohol system and co-precipitation produces a solid solution of the components.

In an attempt to more closely imitate the dry method of preparing tablets containing steroid hormone, the 1: 9 crystalline norgestimate / FAST-FLO lactose mixture was processed by ball milling for 20 minutes. PXRD analysis revealed the absence of crystalline norgestimate. However, there was no visible visual reduction in the lactose crystallinity. The milled mixture was stored at room temperature at 0% RH and at 31% RH and at 40 ° C and 75% RH. Visual assessment revealed that norgestimate remained in said mixture at room temperature in a non-crystalline form for at least 103 days. Recrystallization of norgestimate under accelerated conditions, at higher temperature / humidity, started between 54 and 82 days of storage. The results further support the hypothesis that the non-crystalline form of norgerstimat is physically stabilized by lactose, even in the absence of a detectable modification of the lactose crystallinity. It is also envisaged to dissolve norgestimate more rapidly from the solid solution than is the case with the crystalline form.

A comparison of the dissolution rates and the amount of dissolved components of the samples containing both crystalline and non-crystalline norgestimate was performed using a conventional standard dissolution apparatus (USP apparatus 2, 75 rpm, 600 mL 0.05% Tween 20). Not surprisingly, this preliminary assessment showed different behavior of the two solid forms of norgestimate in this test. The results of the study are shown in Table 1 below.

Table 1

dissolution time amorphous crystalline (min) norgestimat norgestimat 5 0.44 pg / ml 0.43 pg / ml 60 1.38 pg / ml 0.81 pg / ml 120 1.88 pg / ml not specified 140 not specified 1.36 pg / ml

The dissolution rate and the amount of norgestimate dissolved in the dissolution medium after co-grinding norgestimate with lactose at a ratio of 1: 9 were also determined. PXRD analysis showed that norgestimate is non-crystalline after grinding, while lactose is partially crystalline. The parameters of norgestimate dissolution were »· gest gest gest gest gest gest gest gest gest gest gest gest gest gest gest gest gest gest gest gest gest gest gest gest determined according to storage time at about 40 ° C and 75% RH using 100 mL of 0.05% Tween 20 as dissolution medium. The kinetics of recrystallization of the resulting solid solution was monitored by PXRD. Supposedly, the lactose recrystallized between 0 and 2 days. Initiation of norgestimate recrystallization was found between 17 and 22 days. Norgestimat has been partially crystallized for at least 44 days under accelerated storage conditions. The evaluation results are shown in Table 2.

Table 2

dissolution time (min) concentration norgestimatu day = 0 concentration norgestimatu day = 44 10 5.3 pg / ml 2.4 pg / ml 20 May 5.1 pg / ml 5.2 pg / ml 30 6.2 pg / ml 6.5 pg / ml 60 8.7 pg / ml 5.9 pg / ml 240 10 pg / ml 6.7 pg / ml 720 10.3 pg / ml 7.3 pg / ml

These results demonstrate that the dissolution properties of norgestimate in combination with lactose (1: 9 ratio) vary depending on how norgestimat recrystallizes from the metastable solid solution. These results further demonstrate the potential effect of mechanical energy on the solid form of norgestimate and lactose in norgestimate containing tablets.

Differences in the dissolution parameters of the tablets prepared by dry processing were also evaluated both in the pilot study and on the operational scale. By means of the dry treatment method using a rotary drum mixer, the minimum agitated energy can be transferred to the agitated mixture

• · '

0.1 hp-min / kg and additional energy can be added by providing the drum with additional blades or knives. Increasing the processing time using blades or knives makes it possible to deliver enough energy to form the molds of the invention. The results of the dissolution study of both forms prepared at different scale production volumes are shown in Tables 3a and 3b. Along with the increase in the dissolution rates that measure the application of the method of the invention, the results also show that the higher the energy transferred during processing, the higher the levels of less crystalline gestagen. It should also be noted that the dissolution rate is a function of mixing time. The results are shown in the corresponding Tables 3a and 3b.

Table 3a

pilot study amount dissolved mixing time (min) norgestimate after 20 min in% 2.5 74.9 5 78.4 10 85 20 May 88.5 30 97.4 33 93.6

Table 3b

operational scale amount dissolved mixing time (min) norgestimate after 20 min in% 4.8 64.7

Table 3b (continued)

12 81.2 15 Dec 90.3 30 92.8 45 96.2 60 97.4 75 97.2

As can be seen from the results shown in Table 4 below, the relative stability of the dissolution properties of the tablets prepared by the wet process and stored under accelerated storage conditions also depends on the variations in the amount of energy transmitted by mixing. The results presented in Table 4 further support the existence of a high-energy form of norgestimate in the presence of lactose. In addition, Table 4 shows changes in dissolution parameters after storage at 40 ° C at 75% RH. Similar to the results shown in Table 2, the dissolution parameters depend on storage conditions. However, it will be appreciated that the extent of the variation of said parameters also depends on the energies transmitted by the mixing during processing.

Table 4

the amount of norgestimate dissolved after 30 min in% mixing time (min) initial condition after 1 month at 40 ° C / 75% RH 0 75.4 36 2 * 91 45 20 May 90.1 45 40 92, 6 46 60 94.5 85

Based on the above studies, it has been determined that when the mixture of the additive and the steroid active ingredient is subjected to a sufficient amount of mechanical energy, the additive and the steroid active ingredient form a less crystalline composition with a higher energy level. Further, under suitable mixing conditions, the lactose component stabilizes the steroid in said high energy substantially non-crystalline state and thereby prevents recrystallization of the steroids. This is particularly important in the case of a gestagen such as norgestimate, which in a non-crystalline state is completely unstable and prone to rapid recrystallization. The high energy non-crystalline steroid active ingredient dissolves more readily and allows the desired dissolution parameters to be maintained under various humidity and storage conditions. In addition, it has been shown that the high-energy steroid: lactose mixture has a higher recrystallization temperature than the same steroid / lactose mixture under the same conditions but not prepared by high energy intake mixing but with the amorphous state (see Table 7, Example 3). ).

As mentioned above, the mixture is preferably to deliver at least about 0.1 (hp-min) / kg mechanical energy, most preferably at least about 0.12 (hp-min) / kg mechanical energy. Any method of high-energy processing can be used to provide sufficient energy in an embodiment of the invention. One preferred embodiment is an embodiment comprising high energy milling using a device capable of delivering the amount of energy required to carry out the invention. Examples of such devices include a rotary mixing drum provided with an intensification system, a disc mixer provided with a high shear blade or stirrer, or a mixer with a belt stirrer having a suitable energy capacity. The mixing system is operated with parameters suitable for delivering the energy required to carry out the invention.

Alternatively, grinding or comminution methods may be used. This can be achieved using the usual grinding equipment available. Grinding conditions can be varied significantly, usually the mixture is milled for 10-30 minutes, preferably about 20 minutes using a small ball mill.

Although not a critical condition of the process of the invention, it is preferred to control the moisture content prior to and during processing to 55% RH or less in order to further inhibit the crystallization of the components, and it is also preferred that mixing is performed at room temperature.

As already described above, further additives may be added to the mixture, preferably said additives being added to the powder additive prior to mixing with a high energy input. Commonly used additives include: (i) disintegrants such as clays, alginic acid and alginates, celluloses such as microcrystalline cellulose, croscarmellose sodium, cross-linked polymers such as cross-linked polyvinylpyrrolidone (crospovidone) or cross-linked sodium starch, carboxymethylcellulose, sodium starch glycolate, starch and pregelatinized starch; (ii) glidants such as talc, magnesium stearate, calcium stearate, stearic acid, colloidal silica, magnesium carbonate, magnesium oxide, calcium silicate; and dyes such as caramel and D&C and FD&C dyes. Other excipients may include glidants, fillers, binders and the like. The aforementioned excipients as well as other additives or processing aids can be added as desired to prepare a material suitable for processing into a steroid hormone preparation.

The method of the invention is most suitable for preparing oral contraceptives containing one or more steroids, preferably a gestagen, most preferably norgestimate and / or estrogen, preferably ethinyl estradiol as the active ingredient (s). It is also possible according to the invention to prepare oral contraceptives which comprise norgestrel, levonorgestrel, desogestrel, 3-ketodesorgestrel or norethindrone as a gestagen component instead of norgestimate. It is also possible according to the invention to prepare oral contraceptives containing an estrogenic component such as β-estradiol, 17α-ethinylestradiol, estropipat-3-methyl ether and mestranol. However, the method of the invention is applicable to any medicament which contains as an active ingredient a component having low to moderate water solubility that exists in various polymorphic forms, some of which can be stabilized by physical interaction with an excipient such as lactose to provide a faster solubility composition. Furthermore, the method of the invention is particularly well applicable to the preparation of oral contraceptives contained in a kit comprising oral solid dosage forms of varying efficacy in terms of active ingredient content described above. Alternatively, the method of the invention can be used to prepare HRT formulations that also contain estrogen and / or gestagen generally in other combinations of active ingredient content than oral contraceptives.

The invention is described in more detail by way of the following non-limiting examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Dry ground amorphous lactose / norgestimate mixture

Amorphous norgestimate was prepared by dissolving norgestimate (200 mg) in 5 mL of dichloromethane (DCM) and 0.26 mL of ethanol (EtOH). The solution was filtered through a 0.2 µm filter and the solvent was evaporated under reduced pressure to give an amorphous solid.

Mixtures of norgestimate and lactose, in amorphous and crystalline form, are prepared by grinding for 20 minutes. The amorphous state of each component and mixture is verified by powder X-ray diffractometry (PXRD). The results are described below and are summarized in Table 5.

The crystalline norgestimate: crystalline lactose mixture (1: 9) is milled in a Wig-1-Bug mill. A small ball mill provides an amorphous norgestimate with predominantly crystalline lactose while a larger rod mill provides both compounds in crystalline form. Grinding the crystalline norgestimate: crystalline lactose mixture provides partially crystalline norgestimate and partially crystalline lactose.

Grinding also treats a mixture of amorphous norgestimate and amorphous lactose (1: 9). The resulting solid mixture has PXRD parameters corresponding to the amorphous form of both components. Non-crystalline mixtures are also obtained by milling mixtures of amorphous norgestimate and amorphous lactose.

Table 5

Preparation of amorphous norgestimate: lactose by grinding

method ³ norgestimat : lactose sample C. PXRD form ^b PXRD form ^b norgestimat lactose WLB (29) 1: 9 ^C 161-55-01 ³ C C WLB (21) 1: l ^c 256-33-1® PC C

• ·

Table 5 (continued)

WLB (21) 1: 9 ^C 256-33-03® AND C WLB (21) 1: 1 ¹ 268-25-01 ^d AND AND WLB (21) 1: 1 ¹ 314-10-01 ^d AND AND WLB (21) L: 9 ^f 268-24-01 ^d AND AND

a. grinding time of the solid component in minutes in a Wig-L-Bug® mill;

b. C = crystalline; A = amorphous; PC = partially crystalline;

c. both samples were in crystalline form;

d. A small Wig-L-Bug® ball mill was used for grinding;

e. a large Wig-L-Bug® rod mill was used for grinding;

f. both processed samples were in amorphous form;

Example 2

Stability study of amorphous materials.

In this study, amorphous norgestimate has been shown to be stabilized by lactose in a number of norgestimat-containing products: lactose. Stress studies as well as thermal analysis (see Example 3) revealed stabilization of norgestimate in norgestimat: lactose mixtures.

Amorphous norgestimate was prepared from a DCM: EtOH solution, and then its stability under various humidity conditions was evaluated to obtain baseline norgestimate stability values. To simulate the preparation of drugs, non-crystalline norgestimate: lactose mixtures were prepared in one of four ways: by co-precipitation from EtOH: H ₂ O or from

2-BuOH: H ₂ O, by spray drying on amorphous lactose, milling crystalline mixtures, or milling amorphous mixtures. It was also

* · · · · ·

The studied physical stability of the non-crystalline norgestimate to resist recrystallization in the absence of lactose or with the same proportion of lactose.

Materials for each sample were prepared as follows:

Amorphous norgestimat

Norgestimat (200 mg) was dissolved in 5 ml ethanol. The solution is then filtered through a filter by evaporating the solvent under reduced pressure to a solid product.

DCM and 0.26 mL 0.2 µm to give amorphous

Amorphous lactose

FAST-FLO lactose (516 mg) was dissolved in 17 ml H ₂ O and then the solution was filtered through a 0.2 µm filter and lyophilized to dryness. However, the solid product obtained is partially crystalline.

Norgestimate / lactose co-precipitation

Norgestimat (10 mg) and FAST-FLO lactose (91 mg) were dissolved in 143 mL of EtOH 2 O (3.56: 1) and the solution was filtered through a 0.45 µm filter. Evaporation of the solvent under reduced pressure gave an amorphous solid.

Norgestimat (20 mg) and FAST-FLO lactose (180 mg) were dissolved in 65 ml of 2-butanol: water (68:32) and the solution was filtered through a 0.2 µm filter. Evaporation of the solvent under reduced pressure at 30 ° C afforded a non-crystalline solid.

·· ·· «· · · · ·

Norgestimat (10 mg) and FAST-FLO lactose (90 mg) were dissolved at 60 ° C in 29 ml of a 2.6: 1 ACN: H ₂ O solvent mixture and the solution was filtered through a 0.2 µm filter. Evaporation of the solvent under reduced pressure at 35 ° C gave a non-crystalline solid.

Norgestimat / lactose spray drying

The amorphous lactose is introduced into a round-bottomed flask and the flask is connected to a source of reduced pressure. The Norgestimate solution in EtOH: H ₂ O (95: 5) (0.5 mg / ml) was filtered through a 0.2 µm filter and injected into a lactose-containing round-bottom flask with a reduced pressure source attached. Drying the norgestimate solution on the solid lactose surface then provides the desired non-crystalline form of norgestimate.

A solution of the treated amorphous lactose in methanol is added to the TLC silica gel layer and observed with a short wave UV lamp. The stain is UV-active. Lactose alone is not UV-active.

Processing of norgestimate / lactose by grinding

Norgestimat (50 mg) and FAST-FLO lactose (450) are introduced into a Wig-L-Bug mill and grinding the grinding bars for 20 minutes to produce a non-crystalline norgestimate.

Treatment of norgestimate / lactose by mechanical mixing

Norgestimat (2.2 mg) and lactose (2.6 mg) were mixed in the vial with a spatula for 1 minute. An additional portion of lactose (4.6 mg) was then added and stirring was continued with a spatula for an additional 1 minute. The procedure is repeated until all the lactose (9.0 mg, 2.6 mg, total 18.8 mg) is added.

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Stability study of amorphous material

A vial containing a small amount of amorphous material is placed in an air conditioning box containing an aqueous salt solution and the box is sealed. At specified times, the sample is analyzed by the PXRD method.

PXRD

PXRD analyzes were performed on a Shimadzu XRD-6000 X-ray powder diffractometer using a Cu Kα radiation source (1.5406 Å). The device is equipped with a fine-focus X-ray tube. The tube voltage and current are set to 40 kV and 40 mA. The divergent and scattering slots are set to 1 ° and the receiving slot is set to 0.15 mm. The radiation after diffraction is detected by a NaI scintillation detector. A continuous theta-two theta, 3 / min (0.4 s / 0.02 degree) recording from 2.5 to 40 ° 20 is used. Each sample is analyzed on a quartz sample holder.

The results of stability studies are summarized in Table 6.

The results show that the drug models of the invention have excellent physical stability compared to amorphous norgestimate alone. In the absence of lactose, amorphous norgestimate recrystallizes in less than 3 days at 0% relative humidity and less than 1 day at 31% and 76% relative humidity. Co-precipitates from EtOH: H ₂ O or from 2-BuOH: H ₂ O are stable (ie, until the onset of norgestimate recrystallization) up to 90 and 25 days at 0% RH, respectively. In mixtures obtained by spray drying or grinding, norgestimat remains substantially non-crystalline throughout the study (ie 97 days) at 0% or 31%

9

9 9

9

RH. At 76% RH, the grinding mixture obtained in which the norgestimate is stable up to 82 days has the best stability. The ground amorphous mixture in a 1: 1 ratio shows a partially crystalline norgestimate, and still remains partially crystalline after 93 days. From the above studies, it can be concluded that lactose stabilizes norgestimate substantially in its non-crystalline form.

Table 6

Stability of amorphous norgestimate

amorphous sample way amorphous stability norgestimatu 0% RH 31% RH 7 6% RH norgestimate evaporation <3 days <1 day <1 day norgestimate : lactose 1: 9 coprecipitation from EtOH: H ₂ O <90 days <1 day norgestimate : lactose 1: 1 coprecipitation from EtOH: H ₂ O <7 days norgestimate : lactose 1: 9 coprecipitation from 2-BuOH: H ₂ O <25 days <6 days <1 day norgestimate : lactose 1: 9 spray drying from EtOH: H ₂ O > 97 days > 97 days norgestimate : lactose 1: 9 ground crystalline mixture > 103 days > 103 days <82 days norgestimate : lactose 1: 9 ground amorphous mixture > 93 days > 93 days <1 day norgestimate : lactose 1: 1 ground amorphous mixture ^h <1 day ¹ <1 day ¹ <1 day

·· · · · · · · · · ·

Example 3

The lactose / norgestimate mixtures prepared according to Example 2 were evaluated by thermal analysis by differential scanning calorimetry (DSC) performed in a conventional manner.

Determination of glass transition temperature and evaluation of exothermic crystallization

Amorphous materials exhibit glass transition temperatures (T _{g) of} which are an indicator of physical stability of the amorphous form. The stabilized mixtures containing norgestimate: lactose (1: 9) were evaluated simultaneously with the individual amorphous materials in order to gain insights into the stability of the individual mixtures compared to the one-component system. To determine the glass transition temperature, it was generally necessary to perform three successive DSC determinations in order to obtain an optimal method for detecting the glass transition phenomena. Amorphous lactose exhibits a very intense lesions T _g at 114-115 ° C. However, consistent changes were not found in amorphous norgestimate. Some samples of amorphous norgestimate with formation of a weak signal corresponding to T _g at 122-123 ° C, while other samples were noticeable exothermic signal is probably caused by crystallization of norgestimate. All norgestimate samples exhibit a similar endothermic pattern at 226-228 °. Thermogravimetric analysis (TGA) showed a rapid weight loss at this temperature, confirming that the endothermic course at 220 ° C was predominantly related to decomposition. According to the Merck Index, the melting point of crystalline norgestimate is 214-218 ° C.

Another DSC method was used to detect the phenomenon associated with the thermal changes associated with crystallization ···· · ·

norgestimate (Tc). This temperature-related phenomenon (Tc) was used to measure the stability of various modeled drugs. Tc should be higher if lactose is stabilized with norgestimate.

For model drugs simulating medicinal products, this phenomenon was not detected or occurred at a higher temperature (Tc) compared to pure amorphous norgestimate (Table 7). The Tc results are consistent with the results of the stability study and confirm that lactose stabilizes the amorphous norgestimate.

Table 7

Determination of T _c amorphous mixtures

sample T _c amorphous norgestimat 105 ° C norgestimat: lactose, 1: 9, co-precipitate from 2-BuOH: H ₂ O Mp 164 ° C norgestimat: lactose, 1: 1, co-precipitate from 2-BuOH: H ₂ O norgestimat: lactose, 1: 9, spray drying crystalline norgestimate: lactose, 1: 9, grinding 132 [deg.] C amorphous norgestimate: lactose, 1: 9, grinding amorphous norgestimate: lactose, 1: 1, grinding 126 [deg.] C

Example 4

Wet / dry processing

A gestagen such as norgestimate is dissolved in a suitable solvent such as methanol or ethanol. This solution is then applied to a powder bed containing lactose and some other ingredients. Said deposition consists in preparing droplets of solution which are sprayed onto the powder bed while mixing to prevent the formation of clumps. After sufficient time for all application of the solution, the solvent is removed by means of a reduced solvent

pressure and heat. After removal of the predetermined minimum amount of solvent, the mixture is further processed by mixing. The mixing is carried out, for example, in a rotary drum mixer equipped with a stirrer or blade blades, where the mixing is carried out for a time sufficient to impart mechanical energy as described above to obtain a lactose / gestagen powder mixture wherein the gestagen is stabilized in substantially non-crystalline form.

Claims (17)

PATENT CLAIMS What is claimed is: 1. A steroid hormone preparation, characterized in that it has improved solubility and release rate properties, said preparation comprising a steroid hormone substantially in non-crystalline form in admixture with an additive, wherein said additive stabilizes said hormone in its substantially non-crystalline form. The steroidal hormone preparation according to claim 1, characterized in that the basic ingredient is selected from the group consisting of dextrose, fructose, sorbitol, xylitol, sucrose, lactose, mannitol, dextrate, cellulose, starch and mixtures thereof. The steroid hormone preparation according to claim 1, wherein the steroid hormone is at least one hormone selected from the group consisting of gestagen and estrogen. The steroid hormone preparation of claim 3, wherein the steroid hormone is a gestagen selected from the group consisting of norgestimate, norgestrel, levonorgestrel, norethindrone, and desonorgestrel. The steroidal hormone preparation of claim 4, wherein the steroid hormone is norgestimate and the additive is lactose. 6. The steroidal hormone preparation of claim 3, wherein said preparation is a formulation selected from the group consisting of an oral contraceptive and a hormone replacement therapy formulation. The steroidal hormone preparation of claim 6, wherein said preparation is an oral contraceptive containing from about 10 µg to about 50 µg estrogen and / or from about 50 µg to about 300 µg gestagen. The steroidal hormone preparation of claim 7, wherein said gestagen is norgestimate and the additive is lactose. A process for preparing a steroidal hormone preparation having improved solubility and release rate properties, comprising the steps of: preparing a composition comprising at least one steroid hormone and at least one additive; providing a sufficient amount of mechanical energy to said composition to yield an additive / hormone powder composition wherein the hormone is stabilized by said additive in substantially non-crystalline form; and preparing said composition from the prepared powder mixture. 10. The method of claim 9, wherein the mixture is provided with at least 0.1 hp-min / kg of mechanical energy to obtain a powder mixture. Method according to claim 9, characterized in that, in the step in which the mechanical energy is transferred to the mixture, se ·· Φ ΦΦ Φ · Φ · ΦΦΦΦ φφ φ Φ Φ ΦΦΦΦ ΦΦΦΦ Φ φ φ Φ * · Φ φφφφ 31 ................... subject the mixture to high energy mixing. 12. The method of claim 9, wherein the hormone / ingredient ratio in the composition is in a ratio of from about 1/1 to about 1/10. 13. The method of claim 9 wherein the main ingredient is selected from the group consisting of dextrose, fructose, sorbitol, xylitol, sucrose, lactose, mannitol, dextrate, cellulose, starch, and mixtures thereof. 14. The method of claim 9, wherein the steroid hormone is at least one hormone selected from the group consisting of gestagen and estrogen. 15. The method of claim 14 wherein the steroid hormone is a gestagen selected from the group consisting of norgestimate, norgestrel, levonorgestrel, norethindrone, and desonorgestrel. 16. The method of claim 15 wherein the steroid hormone is norgestimate and the additive is lactose. 17. The process of claim 9 wherein the step of preparing the composition comprises the following steps: preparing a solution of the hormone in a suitable solvent; homogenously mixing the solution with the additive; and removing the solvent.